Ricerc@Sapienza

The goal of this project is to define the role of Histone Deacetylase 4 (HDAC4) in Duchenne Muscular Dystrophy (DMD) in order to improve pharmacological treatments presently in use for DMD.
Background/Rationale. DMD is a devastating, genetic disorder characterized by progressive muscle weakness and degeneration. To date, no cure is available for this disease. The general HDAC inhibitor (HDACi) givinostat is presently in phase III clinical trial for the treatment of DMD. However, several limitations are associated with the use of HDACi. HDAC4 is a stress responsive member of class II HDACs that regulates many responses in skeletal muscle, including satellite cell biology and muscle regeneration upon injury. HDAC4 expression is upregulated in skeletal muscle of mdx mice, a murine model for studying DMD, suggesting a role in this disease. However, HDAC4 functions in DMD are uncharacterized yet.
To investigate HDAC4 role in DMD with a genetic approach, we generated mdx mice with a deletion of HDAC4 specifically in skeletal muscle (mdx;HDAC4mKO mice). HDAC4 deletion in skeletal muscle reduced muscle regeneration in mdx mice, hampering satellite cell to properly differentiate in vitro, overall leading to functional deficit. Importantly, HDAC4 mainly localized in the cytoplasm of dystrophic muscles and ectopic expression of the cytoplasmic-restricted form of HDAC4 restores mdx;HDAC4mKO satellite cell differentiation. Here plan to ectopically express the cytoplasmic-restricted form of HDAC4 in vivo in mdx;HDAC4mKO mice, and to evaluate any beneficial effects on muscle regeneration, degeneration and function.
Anticipated output. We speculate that ectopic expression of the cytoplasmic-restricted form of HDAC4 will improve mdx;HDAC4mKO muscle homeostasis, shading new light on the unrecognized role of HDAC4 in skeletal muscle cytoplasm and providing the experimental bases for the development of more effective treatments in combination with pan-HDACi for treating DMD.